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Efficacy and Safety of COVID-19 Vaccines: a Systematic Review and Meta-Analysis of Randomized Clinical Trials

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Efficacy and Safety of COVID-19 Vaccines: a Systematic Review and Meta-Analysis of Randomized Clinical Trials Review Efficacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials Ali Pormohammad 1, Mohammad Zarei 2, Saied Ghorbani 3 , Mehdi Mohammadi 1 , Mohammad Hossein Razizadeh 3 , Diana L. Turner 4 and Raymond J. Turner 1,* 1 Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; [email protected] (A.P.); [email protected] (M.M.) 2 John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; [email protected] 3 Department of Virology, Faculty of Medicine, Iran University of Medical Science, Tehran 1449614535, Iran; [email protected] (S.G.); [email protected] (M.H.R.) 4 Department of Family Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(403)-220-4308 Abstract: The current study systematically reviewed, summarized and meta-analyzed the clinical features of the vaccines in clinical trials to provide a better estimate of their efficacy, side effects and immunogenicity. All relevant publications were systematically searched and collected from major Citation: Pormohammad, A.; Zarei, databases up to 12 March 2021. A total of 25 RCTs (123 datasets), 58,889 cases that received the M.; Ghorbani, S.; Mohammadi, M.; COVID-19 vaccine and 46,638 controls who received placebo were included in the meta-analysis. In Razizadeh, M.H.; Turner, D.L.; Turner, total, mRNA-based and adenovirus-vectored COVID-19 vaccines had 94.6% (95% CI 0.936–0.954) R.J. Efficacy and Safety of COVID-19 and 80.2% (95% CI 0.56–0.93) efficacy in phase II/III RCTs, respectively. Efficacy of the adenovirus- Vaccines: A Systematic Review and vectored vaccine after the first (97.6%; 95% CI 0.939–0.997) and second (98.2%; 95% CI 0.980–0.984) Meta-Analysis of Randomized doses was the highest against receptor-binding domain (RBD) antigen after 3 weeks of injections. Clinical Trials. Vaccines 2021, 9, 467. The mRNA-based vaccines had the highest level of side effects reported except for diarrhea and https://doi.org/10.3390/ arthralgia. Aluminum-adjuvanted vaccines had the lowest systemic and local side effects between vaccines9050467 vaccines’ adjuvant or without adjuvant, except for injection site redness. The adenovirus-vectored and mRNA-based vaccines for COVID-19 showed the highest efficacy after first and second doses, Academic Editors: Soo-Hong Lee, Hansoo Park, Jagathesh respectively. The mRNA-based vaccines had higher side effects. Remarkably few experienced Chandra Rajendran and extreme adverse effects and all stimulated robust immune responses. K.S. Jaganathan Keywords: COVID-19; SARS-CoV-2; vaccines; efficacy; side effect; randomized clinical trial; meta-analysis Received: 5 April 2021 Accepted: 28 April 2021 Published: 6 May 2021 1. Introduction Publisher’s Note: MDPI stays neutral Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a non-segmented with regard to jurisdictional claims in positive-sense, single-stranded ribonucleic acid (RNA) beta coronavirus [1] that was first published maps and institutional affil- reported in Wuhan, China. The SARS-CoV-2 infection causes the coronavirus disease 2019 iations. (COVID-19) that became a global pandemic and public health crisis. Over 140 million infected and 3 million deaths are reported from COVID-19 by April 2021, with the death rate accelerating; according to WHO, the case fatality ratio (CFR) of SARS-CoV-2 ranges from less than 0.1% to over 25% depending on the country [2]. Copyright: © 2021 by the authors. To overcome this pandemic, vaccination is the hope for a safe and effective way to Licensee MDPI, Basel, Switzerland. help build protection and reduce disease spread [3]. More than 200 COVID-19 vaccine This article is an open access article candidates presented in different stages of development and over 50 candidates have distributed under the terms and reached clinical trials to date [4], including: Oxford-AstraZeneca’s ChAdOx1/AZD1222, conditions of the Creative Commons Moderna’s mRNA-1273, Pfizer-BioNTech’s mRNA BNT162b2, Gamaleya’s Sputnik V, Attribution (CC BY) license (https:// Johnson & Johnson’s INJ-7843735/Ad26.COV2.s, CoronaVac, Sinopharm’s BBIBP-CorV, creativecommons.org/licenses/by/ Novavax’s NVX-CoV2373, EpiVacCorona, CanSino’s Convidicea (Ad5-nCoV), SinoVac’s 4.0/). Vaccines 2021, 9, 467. https://doi.org/10.3390/vaccines9050467 https://www.mdpi.com/journal/vaccines Vaccines 2021, 9, 467 2 of 21 CoronaVac, Anhui Zhifei Longcom’s ZF2001, GlaxoSmithKline and Medicago’s CoVLP, and Bharat Biotech’s BBV152/Covaxin. Different strategies have been considered for the development of vaccines against SARS-CoV-2 based on the following vaccine platforms: (I) Nucleic acid mRNA-based vaccines are the newest generation of vaccine production approach [5]. The mRNA vac- cine technology is a single-stranded RNA molecule that carries a portion of the coding sequence for the peptide or protein from the virus that can be synthesized in the cytoplasm (ribosomes). The resulting antigen triggers an immune response, including the production of antibodies [5]. For instance, the current vaccines developed by the companies Pfizer and Moderna utilize synthetic mRNA encoding the sequence of the coronavirus’s signature spike protein (S-protein) that is then encapsulated within a lipid vesicle nanoparticle. (II) Vi- ral vector vaccines that are developed with new biotechnology [6]. A modified existing virus, able to infect human cells, is introduced carrying the genetic code of the target virus antigen in order to stimulate an immune response. Oxford-AstraZeneca, Gamaleya, CanSio and Johnson & Johnson developed their vaccines based on a DNA sequence encoding the S-protein inserted into the genome of a modified safe adenovirus. (III) Whole-Pathogen Inactivated virus vaccines consisting of killed/inactivated whole viruses or virus fragments. Here the pathogen’s genetic material is destroyed by heat, chemicals, or radiation, so that they cannot replicate but their presence can still stimulate immunogenicity [7]. Sinopharm, SinoVac, and Bharat Biotech’s vaccines were produced by inactivating the SARS-CoV-2 with B-propiolactone, but all the viral protein remains intact. (IV) Subunit vaccines that contain a fragment of the pathogen, either a protein (Pro-subunit), a polysaccharide, or a combination of both, without introducing viable pathogen particles [8]. Lack of genetic material makes them safe and non-infectious/non-viable. Novavax and Anhui Zhifei Longcom applied this technology for the development of their vaccine, using nanoparti- cles coated with synthetic S-protein and an adjuvant for boosting the immune response. Virus-like particle (VLP) vaccines, also a subunit vaccine, mimic the native virus structure, but contain no viral genetic material [9]. A VLP presents the antigen inserted on a nanopar- ticle surface. GlaxoSmithKline and Medicago used a plant-derived platform to produce a particle that elicits neutralizing antibody and immune cell (e.g., TH1 T cell) responses against COVID-19. The structural proteins of SARS-CoV-2 include four major proteins: spike (S), mem- brane (M), and envelope (E) part of the viral surface envelope, and the nucleocapsid (N) protein in the ribonucleoprotien core. Among viral surface elements, the S-protein is a primary target for vaccines and therapeutic development against COVID-19 due to its role in the receptor recognition for cell entry and cell membrane fusion process. The trimeric S-protein contains two subunits, S1 and S2. The S1 contains a receptor-binding domain (RBD), which is responsible for recognizing and binding to the host receptor angiotensin- converting enzyme 2 (ACE2), while the S2 mediates the membrane fusion process by forming a six-helical bundle (6-HB) via the two-heptad repeat (HR) regions [10]. However, S1 is the immunodominant antigen during CoV infections and induces long-lasting and broad-spectrum neutralizing antibodies (NAbs) and T-cell immune responses against the RBD. Thus, the S-protein and the RBD serve as the promising targets of SARS-CoV-2 vac- cines and the predominant antigenic target for developing a vaccine [11]. Other antigenic targets, such as non-structural proteins (nsp) 3, nsp8-10 [12], papain-like proteases (PL- pro), and cysteine-like protease (3CLpro) [13] can be considered an alternative for vaccine development, but these are expected to elicit less of an immune response. Efficacy and safety, thus side effect profiles, are core vaccine competencies required by medical care systems and public health. To the best of our knowledge, there is still no com- prehensive comparative study around the efficacy and safety of COVID-19-related vaccines. In this regard, we provide here a meta-analysis on available randomized clinical trial (RCT) publications providing information on the efficacy and side effects of COVID-19 vaccines. Vaccines 2021, 9, 467 3 of 21 2. Methods 2.1. Search Strategy The Preferred Reporting Items for Systematic Reviews and Meta-Analyses State- ment (PRISMA) recommendations were followed in this analysis [14]. We searched all clinical trial publications related to SARS-CoV-2 vaccines from the following databases: Scopus, EMBASE, Medline (via PubMed), and Web of Science. All studies published up to 12 March 2021 were searched without language restriction by three independent reviewers. Search medical subject headings (MeSH) terms used were “Covid-19 Vaccine”,
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